1,4-Bis(substituted-amino)-5,8-dihydroxy-anthraquinones and leuco bases thereof

ABSTRACT

This disclosure describes symmetrical 1,4-bis(substituted-amino)-5,8-dihydroxyanthraquinones useful as chelating agents and for inhibiting the growth of transplanted mouse tumors.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 63,285, filedAug. 2, 1979, now U.S. Pat. No. 4,278,689 which is a division ofapplication Ser. No. 923,602, filed July 11, 1978, now U.S. Pat. No.4,197,249 which is a continuation-in-part of abandoned application Ser.No. 873,040, filed Jan. 30, 1978 which is a continuation-in-part ofabandoned application Ser. No. 824,872, filed Aug. 15, 1977.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new organic compounds and, more particularly,is concerned with novel symmetrical1,4-bis(substituted-amino)-5,8-dihydroxyanthraquinones which may berepresented by the following general formula: ##STR1## wherein Q is adivalent moiety selected from the group consisting of those of theformulae: ##STR2## wherein n is an integer from 2 to 4, inclusive; R₁and R₂ are each individually selected from the group consisting ofhydrogen, alkyl having from 1 to 4 carbon atoms, monohydroxyalkyl havingfrom 2 to 4 carbon atoms and wherein the carbon atom alpha to thenitrogen atom may not bear an hydroxy group, dihydroxyalkyl having from3 to 6 carbon atoms and wherein the carbon atom alpha to the nitrogenatom may not bear an hydroxy group, formyl, alkanoyl having from 2 to 4carbon atoms, trifluoroacetyl and moieties of the formulae: ##STR3##wherein n is an integer from 2 to 4, inclusive, R is alkyl having from 1to 4 carbon atoms, and R₃ and R₄ are each individually selected from thegroup consisting of hydrogen, alkyl having from 1 to 4 carbon atoms, andmonohydroxyalkyl having from 2 to 4 carbon atoms and wherein the carbonatom alpha to the nitrogen atom may not bear an hydroxy group, and R₃and R₄ taken together with their associated N(itrogen) is morpholino,chlomorpholino, piperazino, 4-methyl-1-piperazino or a moiety of theformula: ##STR4## wherein m is an integer from 2 to 6, inclusive; withthe first proviso that the ratio of the total number of carbon atoms tothe sum of the total number of oxygen atoms plus the total number ofnitrogen atoms in the side chains at the 1-position and the 4-positionmay not exceed 4 and with the second proviso that R₁ and R₂ may not bothbe hydrogen or alkyl. Suitable monohydroxyalkyl and dihydroxyalkylgroups contemplated by the present invention are, for example,β-hydroxyethyl, β-hydroxypropyl, γ-hydroxypropyl, 2,3-dihydroxypropyl,2,4-dihydroxybutyl, and the like. Also included within the purview ofthe present invention are the leuco bases and tautomers thereof whichmay be represented by the following general formulae: ##STR5## whereinR₁, R₂ and Q are as hereinabove defined.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention are obtainable as reddishbrown to blue black crystalline materials having characteristic meltingpoints and absorption spectra and which may be purified by leaching withlower alkanols since many of the free bases are insoluble in water andsome of them are insoluble in most organic solvents. The organic basesof this invention (I, II and III) form non-toxic acid-addition saltswith a variety of pharmacologically acceptable organic and inorganicsalt-forming reagents. Thus, acid-addition salts, formed by admixture ofthe organic free base with 1,2 or up to eight equivalents of an acid,suitably in a neutral solvent, are formed with such acids as sulfuric,phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, malic,succinic, tartaric, acetic, benzoic, gluconic, ascorbic, and the like.For purposes of this invention the free bases are equivalent to theirnon-toxic acid-addition salts. The acid-addition salts of the organicbases of the present invention are, in general, crystalline solids,relatively soluble in water, methanol and ethanol but relativelyinsoluble in non-polar organic solvents such as diethyl ether, benzene,toluene, and the like.

The novel compounds of the present invention may be readily prepared inaccordance with the following reaction scheme: ##STR6## wherein R₁, R₂and Q are as hereinabove defined. In accordance with this reactionscheme, leuco 1,4,5,8-tetrahydroxyanthraquinone (IV) is condensed withan appropriate alkylene diamine (V) in a solvent such asN,N,N',N"-tetramethylethylenediamine, methanol, ethanol, water,dimethylformamide, or mixtures thereof at from about 40° C. to about 60°C. under an atmosphere of nitrogen for several hours to produce thecorresponding leuco bases (II). The leuco bases (II) may be readilyoxidized to the fully aromatic derivatives (I) by a variety of methodssuch as air oxidation or treatment with hot nitrobenzene, or treatmentwith chloranil, hydrogen peroxide, or sodium perborate.

The novel compounds described herein are useful as chelating, complexingor sequestering agents. The complexes formed with polyvalent metal ionsare particularly stable and usually soluble in various organic solvents.These properties, of course, render them useful for a variety ofpurposes wherein metal ion contamination presents a problem; e.g., asstabilizers in various organic systems such as saturated and unsaturatedlubricating oils and hydrocarbons, fatty acids and waxes, whereintransition metal ion contamination accelerates oxidative deteriorationand color formation. They are further useful in analyses of polyvalentmetal ions which may be complexed or extracted by these materials and asmetal carriers. Other uses common to sequestering agents are alsoapparent for these compounds. In addition, the leuco bases (Ii) areuseful as intermediates in the preparation of the fully aromaticderivatives (I).

The novel compounds of the present invention also possess the propertyof inhibiting the growth of transplanted mouse tumors as established bythe following tests.

Lymphocytic leukemia P388 test

The animals used are DBA/2 mice all of one sex, weighing a minimum of 17g. and all within a 3 gram weight range. There are 5 or 6 animals pertest group. The tumor transplant is by intraperitoneal injection of 0.1ml. of dilute ascitic fluid containing 10⁶ cells of lymphocytic leukemiaP388. The test compounds are administered intraperitoneally on days one,5 and 9 (relative to tumor inoculation) at various doses. The animalsare weighed and survivors are recorded on a regular basis for 30 days.The median survival time and the ratio of survival time for treated(T)/control (C) animals are calculated. The positive control compound is5-fluorouracil given as a 60-mg./kg. injection. The results of this testwith representative compounds of the present invention appear in TableI. The criterion for efficacy is T/C×100≧125%.

                  TABLE I                                                         ______________________________________                                        Lymphocytic Leukemia P388 Test                                                                           Median                                                                Dose    Survival T/C ×                                                  mg./    Time     100                                       Compound           kg.     (Days)   (Percent)                                 ______________________________________                                        Leuco-1,4-bis[(2-dimethylamino-                                                                  100     24.5     245                                       ethyl)amino]-5,8-dihydroxy-                                                                      50      24.5     245                                       anthraquinone      25      19.0     190                                                          12      17.5     175                                                          6       16.0     160                                                          3       14.5     145                                                          1.5     13.0     130                                       Control            0       10.0     --                                        5-Fluorouracil     60      19.0     190                                       1,4-Bis[(2-dimethylaminoethyl)-                                                                  50      25.0     278                                       amino]-5,8-dihydroxy-anthraquinone                                                               25      20.5     228                                                          12      23.0     256                                                          6       21.0     233                                                          3       19.5     217                                       Control            0       9.0      --                                        5-Fluorouracil     60      19.5     217                                       Leuco-1,4-bis(2-morpholinoethyl-                                                                 200     13.0     137                                       amino)-5,8-dihydroxy-anthraquinone                                                               100     12.0     126                                                          50      11.0     116                                                          25      12.0     126                                       Control            0       9.5      --                                        5-Fluorouracil     60      19.5     205                                       1,4-Bis(2-morpholinoethylamino)-                                                                 200     14.0     147                                       5,8-dihydroxy-anthraquinone                                                                      100     12.0     126                                       Control            0       9.5      --                                        5-Fluorouracil     60      19.5     205                                       Leuco-1,4-bis[(2-diethylamino-                                                                   200     17.0     179                                       ethyl)amino]-5,8-dihydroxy-anthra-                                                               100     17.0     179                                       quinone            50      15.0     158                                                          25      13.0     137                                                          12      12.0     126                                       Control            0       9.5      --                                        5-Fluorouracil     60      19.5     205                                       1,4-Bis[(2-diethylaminonoethyl)-                                                                 200     20.0     210                                       amino]-5,8-dihydroxy-anthraquinone                                                               100     18.0     189                                                          50      15.0     158                                                          25      16.0     168                                                          12      12.0     126                                       Control            0       9.5      --                                        5-Fluorouracil     60      19.5     205                                       Leuco-1,4-bis[[2-(1-pyrrolidinyl)-                                                               200     23.0     209                                       ethyl]amino]-5,8-dihydroxy-anthra-                                                               100     19.0     173                                       quinone            50      16.0     145                                                          25      15.0     136                                       Control            0       11.0     --                                        5-Fluorouracil     60      20.0     182                                       1,4-Bis[[2-(1-pyrrolidinyl)ethyl]-                                                               100     24.0     218                                       amino]-5,8-dihydroxy-anthraquinone                                                               50      23.0     209                                                          25      21.0     191                                                          12      18.0     164                                       Control            0       11.0     --                                        5-Fluorouracil     60      20.0     182                                       1,4-Bis[(3-dimethylaminopropyl)-                                                                 50      15.5     129                                       amino]-5,8-dihydroxy-anthraquinone                                                               25      15.5     129                                                          12      15.0     125                                       Control            0       12.0     --                                        5-Fluorouracil     60      19.5     162                                       Leuco-1,4-bis[(2-aminoethyl)-                                                                    100     19.0     158                                       amino]-5,8-dihydroxy-anthraquinone                                                               50      23.0     192                                                          25      19.0     158                                                          12      18.0     150                                       Control            0       12.0     --                                        5-Fluorouracil     60      19.5     162                                       Leuco-1,4-bis(3-aminopropylamino)-                                                               200     18.0     150                                       5,8-dihydroxy-anthraquinone                                                                      100     18.0     150                                                          50      16.0     133                                                          25      18.0     150                                                          12      16.0     133                                       Control            0       12.0     --                                        5-Fluorouracil     60      19.5     162                                       Leuco-1,4-bis[2-(2-methylamino-                                                                  200     2.0        18.0                                    ethylamino)ethylamino]-5,8-dihy-                                                                 100     26.0       236.0                                   droxyanthraquinone 50      28.0       255.0                                                      1       21.0       191.0                                                      12.5    16.0       145.0                                                      6.2     15.0     136                                       Control            0       11.0     --                                        5-Fluorouracil     60      17.0     170                                       Leuco-1,4-bis[2-dimethylaminopro-                                                                200     18.0     203                                       pylamino]-5,8-dihydroxyanthraqui-                                                                100     15.0     167                                       none               50      14.0     156                                                          25      13.0     144                                                          12.5    11.0     122                                       Control            0       9.0      --                                        5-Fluorouracil     60      18.5     206                                       1,4-Bis[2-(2-hydroxyethylamino)                                                                  12.5    13.0     130                                       ethylamino]-5,8-dihydroxyanthra-                                                                 6.2     20.0     200                                       quinone Dihydrochloride                                                                          3.1     22.0     220                                                          1.5     >29.0    >290                                                         0.78    >29.0    >290                                                         0.39    27.0     270                                                          0.19    25.0     250                                                          0.09    21.0     210                                                          0.04    20.0     200                                       Control            0       10.0     --                                        5-Fluorouracil     60      20.0     200                                       Leuco-1,4-bis[2-(1-piperazinyl)                                                                  200     7.0       78                                       ethylamino]-5,8-dihydroxyanthra-                                                                 100     21.0     233                                       quinone            50      16.0     178                                                          25      15.0     167                                                          12.5    14.0     156                                       Control            0       9.0      --                                        5-Fluorouracil     60      18.5     206                                       1,4-Bis[2-(methylamino)ethylamino]-                                                              25      9.0       86                                       5,8-dihydroxyanthraquinone                                                                       12.5    16.0     152                                       dihydrochloride    6.2     20.0     190                                                          3.1     22.0     210                                                          1.5     22.5     214                                                          0.78    18.5     176                                                          0.39    19.5     186                                                          0.19    18.5     176                                                          0.09    18.0     171                                                          0.04    17.0     162                                       Control            0       10.5     --                                        5-Fluorouracil     60      18.0     171                                       Leuco-1,4-bis[2-(2-hydroxyethylamino)                                                            25      12.0     114                                       ethylamino]-5,8-dihydroxy-                                                                       12.5    23.5     224                                       anthraquinone      6.2     23.0     219                                                          3.1     26.0     248                                                          1.5     >30.0    >280                                                         0.78    28.0     267                                                          0.39    22.0     209                                                          0.19    21.5     205                                                          0.09    21.5     205                                                          0.04    18.5     176                                       Control            0       10.5     --                                        5-Fluorouracil     60      18.0     171                                       Leuco-1,4-bis(4-aminobutyl-                                                                      400     20.0     190                                       amino)-5,8-dihydroxyanthra-                                                                      300     18.0     171                                       quinone            200     17.0     162                                                          100     14.0     133                                       Control            0       10.5     --                                        5-Fluorouracil     60      17.5     162                                       Leuco-1,4-bis[2-(methyl-                                                                         50      6.0       55                                       amino)ethylamino]-5,8-                                                                           25      19.0     173                                       dihydroxyanthraquinone                                                                           12.5    19.0     173                                                          6.2     21.0     191                                                          3.1     15.0     136                                                          1.5     13.0     118                                       Control            0       11.0     --                                        5-Fluorouracil     60      18.5     168                                       Leuco-1,4-bis[2-(2-isopropyl-                                                                    100     8.0       73                                       amino)ethylamino]-5,8-dihy-                                                                      50      19.0     173                                       droxyanthraquinone 25      17.0     155                                                          12.5    15.0     136                                       Control            0       11.0     --                                        5-Fluorouracil     60      20.5     186                                       1,4-Bis[2-(2-aminoethylamino)                                                                    200     17.0     162                                       ethylamino]-5,8-dihydroxyanth-                                                                   100     16.0     152                                       raquinone          50      14.0     133                                                          25      13.0     124                                       Control            0       10.5     --                                        5-Fluorouracil     60      17.0     162                                       Leuco-1,4-[2-[di(β-hydroxy-                                                                 200     19.0     190                                       ethyl)amino]ethylamino-5,8-                                                                      100     17.0     170                                       dihydroxyanthraquinone                                                                           50      16.0     160                                                          25      15.0     150                                                          12.5    13.5     135                                                          6.2     12.0     120                                       Control            0       10.0     --                                        5-Fluorouracil     40      18.0     180                                       1,4-Bis[2-(2-hydroxy-1-pro-                                                                      25      12.0     120                                       pylamino)ethylamino]1,4-di-                                                                      12.5    24.0     240                                       hydroxyanthraquinone dihy-                                                                       6.2     23.0     230                                       drochloride        3.1     22.0     220                                                          1.56    19.0     190                                                          0.78    19.0     190                                                          0.39    17.5     175                                       Control            0       10.0     --                                        5-Fluorouracil     40      18.0     180                                       1,4-Bis[2,[2-(1-morpholino)ethyl-                                                                200     9.5       95                                       amino]ethylamino]5,8-dihydroxyan-                                                                100     20.0     200                                       thraquinone tetrahydrochloride                                                                   50      18.5     185                                                          25      19.5     195                                                          12.5    15.0     150                                                          6.2     14.0     140                                                          3.1     13.0     130                                       Control            0       10.0     --                                        5-Fluorouracil     40      18.0     180                                       1,4-Bis[2-(3-hydroxy-1-propyl-                                                                   25      8.5       77                                       amino)ethylamino]5,8-dihydroxy-                                                                  12.5    >30.0    >273                                      anthraquinone dihydrochloride                                                                    6.25    26.0     236                                                          3.1     25.0     227                                                          1.56    22.0     200                                                          0.78    21.5     195                                       Control            0       11.0     --                                        5-Fluorouracil     40      18.0     164                                       Leuco-1,4-bis[2-(3-hydroxy-1-                                                                    200     14.0     127                                       propylamino)ethylamino]5,8-                                                                      100     38.0     345                                       dihydroxyanthraquinone                                                                           50      34.0     309                                                          25      22.0     200                                                          12.5    19.5     177                                                          6.25    16.5     150                                                          3.1     18.5     168                                                          1.56    19.5     177                                                          0.78    18.0     164                                       Control            0       11.0     --                                        5-Fluorouracil     40      17.0     155                                       1,4-Bis[2-[di(β-hydroxyethyl)-                                                              200     >30.0    >333                                      amino]ethylamino]5,8-dihydrox-                                                                   100     22.0     244                                       yanthraquinone dihydrochloride                                                                   50      20.5     228                                                          25      21.5     239                                                          12.5    18.5     206                                                          6.2     18.5     206                                                          3.1     19.0     211                                                          1.56    16.0     178                                                          0.78    14.5     161                                       Control            0       9.0      --                                        5-Fluorouracil     60      20.5     228                                       Leuco-1,4-bis[3-(2-hydroxy-                                                                      200     33.5     305                                       ethylamino)-1-propylamino]-                                                                      100     27.5     250                                       5,8-dihydroxyanthraquinone                                                                       50      25.0     227                                                          25      18.5     168                                                          12.5    19.0     173                                                          6.25    18.0     164                                                          3.12    15.0     136                                       Control            0       11.0     --                                        5-Fluorouracil     40      17.5     159                                       Leuco-1,4-bis[2-(2-hydroxy-                                                                      200     9.0       82                                       1-propylamino)ethylamino]-                                                                       100     26.5     241                                       1,4-dihydroxyanthraquinone                                                                       50      24.0     218                                                          25      20.5     186                                                          12.5    21.5     195                                                          6.25    20.0     182                                       Control            0       11.0     --                                        5-Fluorouracil     40      17.5     159                                       1,4-Bis[3-(2-hydroxyethyl-                                                                       100     12.5     114                                       amino)-1-propylamino]5,8-                                                                        50      32.0     291                                       dihydroxyanthraquinone                                                                           25      26.5     241                                       dihydrochloride    12.5    22.5     205                                                          6.25    19.0     173                                                          3.12    19.0     173                                                          1.56    16.0     145                                                          0.78    15.0     156                                       Control            0       11.0     --                                        5-Fluorouracil     40      17.5     159                                       1,4-Bis[2-(1-aziridino)ethyl-                                                                    100     28.5     285                                       amino]-5,8-dihydroxyanthra-                                                                      50      21.5     215                                       quinone            25      20.0     200                                                          12.5    20.5     205                                                          6.25    18.5     185                                                          3.12    19.5     195                                                          1.56    17.0     170                                                          0.78    14.0     140                                       Control            0                --                                        5-Fluorouracil     60      20.5     205                                       1,4-Bis[2-(2-methylaminoethyl-                                                                   100     22.0     220                                       amino)ethylamino]-5,8-dihydrox-                                                                  50      22.0     220                                       yanthraquinone tetrahydrochloride                                                                25      19.5     195                                                          12.5    17.0     170                                                          6.25    16.0     160                                                          1.12    13.5     135                                                          1.56    13.0     130                                       Control            0       10.0     --                                        5-Fluorouracil     40      16.0     160                                       1,4-Bis(2-aminoethylamino)-                                                                      12.5    8.0       73                                       5,8-dihydroxyanthraquinone                                                                       6.2     15.5     141                                       dihydrochloride    3.1     30.0     273                                                          1.56    20.0     182                                                          0.78    24.5     223                                                          0.39    25.5     232                                                          0.19    23.0     209                                       Control            0       11.0     --                                        5-Fluorouracil     60      20.5     186                                       ______________________________________                                    

Lymphocytic leukemia P388 test

The procedure used is the same as for the previously described test forlymphocytic leukemia P388 except that the test compounds areadministered orally at various doses rather than intraperitoneally. Theresults of this test with typical compounds of the present inventionappear in Table II. The criterion for efficacy is T/C×100≧125%.

                  TABLE II                                                        ______________________________________                                        Lymphocytic Leukemia P388 Test (Oral Drug Administration)                                                Median                                                                        Survi-                                                                Dose    val                                                                   mg./    Time    T/C × 100                            Compound           kg.     (Days)  (Percent)                                  ______________________________________                                        Leuco-1,4-bis[(2-dimethylamino-                                                                  50      16.0    160                                        ethyl)amino]-5,8-dihydroxy-anthra-                                                               25      13.5    135                                        quinone            12      12.5    125                                        Control            0       10.0    --                                         5-Fluorouracil*    60      19.0    190                                        1,4-Bis[(2-dimethylaminoethyl)-                                                                  12      16.0    139                                        amino]-5,8-dihydroxy-anthraquinone                                                               6       16.0    139                                                           3       15.0    130                                        Control            0       11.5    --                                         5-Fluorouracil*    60      20.0    174                                        ______________________________________                                         *5-Fluorouracil administered intraperitoneally.                          

Melanotic Melanoma B16

The animals used are C57BC/6 mice, all of the same sex, weighing aminimum of 17 g. and all within a 3-g. weight range. There are normally10 animals per test group. A one-gram portion of melanotic melanoma B16tumor is homogenized in 10 ml. of cold balanced salt solution and a0.5-ml. aliquot of the homogenate is implanted intraperitoneally intoeach of the test mice. The test compounds are administeredintraperitoneally on days one through 9 (relative to tumor inoculation)at various doses. The animals are weighed and survivors are recorded ona regular basis for 60 days. The median survival time and the ratio ofsurvival time for treated (T)/control (C) animals are calculated. Thepositive control compound is 5-fluorouracil given as a 20-mg./kg.injection. The results of this test with representative compounds of thepresent invention appear in Table III. The criterion for efficacy isT/C×100≧125%.

                  TABLE III                                                       ______________________________________                                        Melanotic Melanoma B16 Test                                                                              Median                                                                Dose    Survival T/C ×                                                  mg./    Time     100                                       Compound           kg.     (Days)   (Percent)                                 ______________________________________                                        Leuco-1,4-bis[(2-dimethylamino-                                                                  25      25.0     151                                       ethyl)amino]-5,8-dihydroxy-anthra-                                                               12      23.0     139                                       quinone            6       21.5     130                                                          3       21.0     127                                       Control            0       16.5     --                                        5-Fluorouracil     20      25.0     151                                       1,4-Bis[(2-dimethylaminoethyl)-                                                                  25      24.5     136                                       amino]-5,8-dihydroxy-anthraquinone                                                               12      28.5     158                                                          6       27.0     150                                                          3       25.5     142                                       Control            0       18.0     --                                        5-Fluorouracil     20      26.0     144                                       Leuco-1,4-bis[(2-diethylamino-                                                                   50      23.0     139                                       ethyl)amino]-5,8-dihydroxy-anthra-                                            quinone                                                                       Control            0       16.5     --                                        5-Fluorouracil     20      25.0     151                                       1,4-Bis[(2-diethylaminoethyl)-                                                                   50      20.5     125                                       amino]-5,8-dihydroxy-anthraquinone                                            Control            0       16.5     --                                        5-Fluorouracil     20      25.0     151                                       Leuco-1,4-bis[[2-(1-pyrrolidinyl)-                                                               50      23.0     144                                       ethyl]amino]-5,8-dihydroxy-anthra-                                                               25      22.0     137                                       quinone            12      21.0     131                                       Control            0       16.0     --                                        5-Fluorouracil     20      26.5     166                                       1,4-Bis[[2-(1-pyrrolidinyl)ethyl]-                                                               25      24.5     153                                       amino]-5,8-dihydroxy-anthraquinone                                                               12      22.0     137                                                          6       22.0     137                                       Control            0       16.0     --                                        5-Fluorouracil     20      26.5     166                                       1,4-Bis[(3-dimethylaminopropyl]-                                                                 25      20.0     125                                       amino]-5,8-dihydroxy-anthraquinone                                            Control            0       16.0     --                                        5-Fluorouracil     20      26.5     166                                       Leuco-1,4-bis[(2-aminoethyl)-                                                                    12      32.0     200                                       amino]-5,8-dihydroxy-anthraquinone                                            Control            0       16.0     --                                        5-Fluorouracil     20      26.5     166                                       Leuco-1,4-bis(3-aminopropylamino)-                                                               50      31.5     197                                       5,8-dihydroxy-anthraquinone                                                                      25      27.0     169                                                          12      23.5     147                                                          6       22.5     141                                       Control            0       16.0     --                                        5-Fluorouracil     20      26.5     166                                       Leuco-1,4-bis[2-(2-methylamino-                                                                  50      12.5      73                                       ethylamino]-5,8-dihydroxyanthra-                                                                 25      35.0     206                                       quinone            12.5    39.5     232                                                          6.2     28.5     168                                       Control            0       17.0     --                                        5-Fluorouracil     20      30.0     176                                       Leuco-1,4-bis[2-(1-piperazinyl)                                                                  50      34.5     203                                       ethylamino]-5,8-dihydroxyanthra-                                                                 25      30.5     179                                       quinone            12.5    26.0     153                                                          6       22.0     129                                                          3       20.5     121                                       Control            0       17.0     --                                        5-Fluorouracil     20.0    30       176                                       1,4-Bis[2-(2-aminoethylamino)                                                                    50      24.0     150                                       ethylamino]-5,8-dihydroxyanthra-                                                                 25      22.5     141                                       quinone            12      22.0     138                                                          6       20.0     125                                       Control            0       16.0     --                                        5-Fluorouracil     20      27.0     169                                       Leuco-1,4-bis[2-dimethylamino-                                                                   100     21.0     124                                       propylamino]-5,8-dihydroxyanthra-                                                                50      28.5     168                                       quinone            25      24.5     144                                                          12.5    20.5     121                                                          6       19.5     115                                       Control            0       17.0     --                                        5-Fluorouracil     20      30.0     176                                       1,4-Bis[2-(2-hydroxyethylamino)                                                                  12      11.0      73                                       ethylamino]-5,8-dihydroxyanthra-                                                                 6       15.0     100                                       quinone dihydrochloride                                                                          3       >28.5    >190                                                         1.5     >34.0    >227                                                         0.7     >34.0    >227                                                         0.3     34.0     227                                       Control            0       15.0     --                                        5-Fluorouracil     60      23.0     153                                       Leuco-1,4-bis[2-(2-isopropylamino)                                                               50      6.5       39                                       ethylamino]-5,8-dihydroxyanthra-                                                                 25      31.0     188                                       quinone            12      30.0     182                                                          6       25.0     151                                       Control            0       16.5     --                                        5-Fluorouracil     20      16.5     100                                       1,4-Bis[2-(methylamino)ethyl-                                                                    12.5    11.5      59                                       amino]-5,8-dihydroxyanthra-                                                                      6.2     26.5     136                                       quinone dihydrochloride                                                                          3.1     49.0     251                                                          1.5     33.0     169                                                          0.78    35.0     179                                                          0.39    25.0     128                                                          0.19    29.5     151                                       Control            0       19.5     --                                        5-Fluorouracil     60      25.0     128                                       Leuco-1,4-bis(4-aminobutyl-                                                                      100     21.0     124                                       amino)-5,8-dihydroxyanthra-                                                                      50      20.0     118                                       quinone            25      18.5     109                                                          12      16.0      94                                       Control            0       17.0     --                                        5-Fluorouracil     20      30.0     176                                       Leuco-1,4-bis[2-(2-hydroxy-                                                                      6       9.5       59                                       ethylamino)ethylamino]-5,8-                                                                      3       20.5     128                                       dihydroxyanthraquinone                                                                           1.5     30.0     187                                                          0.75    28.5     178                                                          0.37    22.0     137                                       Control            0       16.0     --                                        5-Fluorouracil     20      27.5     172                                       Leuco-1,4-bis[2-(methylamino)                                                                    12      28.0     175                                       ethylamino]-5,8-dihydroxyanthra-                                                                 6       32.5     203                                       quinone            3       31.0     194                                                          1.5     36.0     225                                                          0.7     27.5     172                                       Control            0       16.0     --                                        5-Fluorouracil     20      27.5     172                                       ______________________________________                                    

Ridgway Osteogenic Sarcoma

The animals used are AKD₂ F₁ /J mice, all of the same sex, weighing aminimum of 17 g. and all within a three-gram weight range. There arenormally 8 animals per test group. The tumor is administeredsubcutaneously by trocar as five 2-mm. fragments per mouse. The testcompounds are administered intraperitoneally every 4 days for a total of6 inoculations beginning on day 15 (relative to tumor inoculation) atvarious doses. The animals are weighed and survivors are recorded on aregular basis for 90 days. The regression of tumors is recorded in alltest animals. Table IV gives the result of this test with arepresentative compound of this invention in terms of the percentage ofanimals showing tumor regression.

                                      TABLE IV                                    __________________________________________________________________________    Ridgway Osteogenic Sarcoma                                                                                                         63 Days After                          1 Day Before                                                                             7 Days After Therapy Stopped                                                                              Therapy Stopped                        Therapy    No. Without          % Showing                                                                            Median                            Dose No. Mice                                                                            Tumor                                                                              Tumors/No.                                                                           Tumor % Inhibition                                                                          50% Tumor                                                                            Survival                                                                           T/C                 Compound (mg./kg.)                                                                          Per Group                                                                           (mm.) 2                                                                            Survivors                                                                            (mm.) 2                                                                             Tumor Growth                                                                          Regression                                                                           (Days)                                                                             (Percent)           __________________________________________________________________________    Placebo  --   8     64   0/5    1189          0      44.5                     1,4-Bis[(2-di-                                                                         100  7     77   2/5    52    96      29     48   108                 methylamino-                                                                           50   8     68   2/6    263   78      25     92.5 208                 ethyl)amino]-                                                                          25   8     82   0/8    653   41      0      78   175                 5,8-dihydroxy-                                                                         12   7     84   0/3    470   61      0      37    83                 anthraquinone                                                                          6    7     83   0/6    960   19      0      57.5 129                 Methotrexate                                                                           25   8     51   1/6    546   54      12     52.5 118                          12   8     52   0/5    916   23      0      40   110                          6    8     54   0/4    758   36      0      46   103                 Vincristine                                                                            1.5  8     42   4/4    0     100     100    68   153                          1.0  6     99   6/6    0     100     100    85   191                          0.5  7     94   4/7    77    93      57     83   186                 __________________________________________________________________________

A preferred embodiment of the present invention may be represented bythe following general formula: ##STR7## wherein Q is as hereinbeforedefined; R₁ is hydrogen, alkyl having from 1 to 4 carbon atoms ormonohydroxyalkyl having from 2 to 4 carbon atoms and wherein the carbonatom alpha to the nitrogen atom may not bear an hydroxy group; R₂ ismonohydroxyalkyl having from 2 to 4 carbon atoms and wherein the carbonatom alpha to the nitrogen atom may not bear an hydroxy group,dihydroxyalkyl having from 3 to 6 carbon atoms and wherein the carbonatom alpha to the nitrogen atom may not bear an hydroxy group or amoiety of the formula: ##STR8## wherein n, R₃ and R₄ are as hereinbeforedefined; with the proviso that the ratio of the total number of carbonatoms to the sum of the total number of oxygen atoms plus the totalnumber of nitrogen atoms in each of the side chains at the 1-positionand the 4-position may not exceed four. The preferred embodimentincludes the corresponding leuco bases of the aromatic bases (I), thetautomers thereof, and the non-toxic pharmaceutically acceptableacid-addition salts thereof.

Another preferred embodiment of the present invention may be representedby the following general formula: ##STR9## wherein n is an integer from2 to 4, inclusive, and R₁ and R₂ are as defined for the precedingpreferred embodiment with the proviso that the ratio of the total numberof carbon atoms to the sum of total number of oxygen atoms plus thetotal number of nitrogen atoms in each of the side chains at the1-position and the 4-position may not exceed four. This preferredembodiment also includes the corresponding leuco bases of the aromaticbases (V), the tautomers thereof, and the non-toxic pharmaceuticallyacceptable acid-addition salts thereof.

Also embraced within the purview of the present invention aretherapeutic compositions of matter useful for ameliorating cancerdiseases in mammals and containing certain5,8-dihydroxy-1,4-bis(substituted-amino)anthraquinones (or the leucobases and non-toxic acid-addition salts thereof) which may berepresented by the following structural formula: ##STR10## wherein R₁ ishydrogen or alkyl having from 1 to 4 carbonatoms, R₂ is hydrogen oralkyl having from 1 to 4 carbon atoms, R₁ and R₂ taken together withtheir associated N(itrogen) is as hereinbefore defined for R₃ and R₄taken together with their associated N(itrogen), and Q is ashereinbefore defined. This aspect of the invention includes the novelcompositions of matter and the method of inducing the regression and/orpalliation of leukemia and related cancers in mammals therewith.

The active ingredients of the therapeutic compositions and the novelcompounds of the present invention inhibit transplanted mouse tumorgrowth and induce regression and/or palliation of leukemia and relatedcancers in mammals when administered in amounts ranging from about 5 mg.to about 200 mg. per kilogram of body weight per day. A preferred dosageregimen for optimum results would be from about 5 mg. to about 50 mg.per kilogram of body weight per day, and such dosage units are employedthat a total of from about 350 mg. to about 3.5 grams of the activecompound for a subject of about 70 kg. of body weight are administeredin a 24-hour period. This dosage regimen may be adjusted to provide theoptimum therapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduce as indicatedby the exigencies of the therapeutic situation. A decided practicaladvantage is that the active compound may be administered in anyconvenient manner such as by the oral, intravenous, intramuscular, orsubcutaneous routes.

The active compounds may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or they may beenclosed in hard or soft shell gelatin capsules, or they may becompressed into tablets, or they may be incorporated directly with thefood of the diet. For oral therapeutic administration, the activecompounds may be incorporated with excipients and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Theprecentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2 to about 60% of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween about 5 and 200 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or broth. A syrup or elixir may contain the active compound,sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed. In addition, the active compounds may be incorporated intosustained-release preparations and formulations.

The active compounds may also be administered parenterally orintraperitoneally. Solutions of the active compound as a free base orpharmacologically acceptable salt can be prepared in water suitablymixed with a surfactant such as hydroxypropylcellulose. Dispersions canalso be prepared in glycerol, liquid polyethylene glycols, and mixturesthereof and in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporanous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), suitable mixtures thereof,and vegetable oils. The proper fluidity can be maintained, for example,by the use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and the freeze-dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

As used herein, "pharmaceutically acceptable carrier" includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutical active substances is well knownin the art. Except insofar as any conventional media or agent isincompatable with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the mammalian subjects to be treated; eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. The specification for the novel dosageunit forms of the invention are dictated by and directly dependent on(a) the unique characteristics of the active material and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding such an active material for the treatment ofdisease in living subjects having a diseased condition in which bodilyhealth is impaired as herein disclosed in detail.

The principal active ingredient is compounded for convenient andeffective administration in effective amounts with a suitablepharmaceutically-acceptable carrier in dosage unit form as hereinbeforedisclosed. A unit dosage form can, for example, contain the principalactive compound in amounts ranging from about 0.1 to about 400 mg., withfrom about one to about 30 mg. being preferred. Expressed inproportions, the active compound is generally present in from about 0.1to about 400 mg./ml. of carrier. In the case of compositions containingsupplementary active ingredients, the dosages are determined byreference to the usual dose and manner of administration of the saidingredients.

Regression and palliation of cancers are attained, for example, usingintraperitoneal administration. A single intravenous dosage or repeateddaily dosages can be administered. Daily dosages up to about 5 or 10days are often sufficient. It is also possible to dispense one dailydosage or one dose on alternate or less frequent days. As can be seenfrom the dosage regimens, the amount of principal active ingredientadministered is a sufficient amount to aid regression and palliation ofthe leukemia or the like, in the absence of excessive deleterious sideeffects of a cytotoxic nature to the hosts harboring the cancer. As usedherein, cancer disease means blood malignancies such as leukemia, aswell as other solid and non-solid malignancies such as themelanocarcinomas, lung carcinomas, and mammary tumors. By regression andpalliation is meant arresting or retarding the growth of the tumor orother manifestation of the disease compared to the course of the diseasein the absence of treatment.

This invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1Leuco-1,4-bis[(2-dimethylaminoethyl)amino]-5,8-dihydroxy-anthraquinone

A reaction mixture comprising 10.58 g. of N,N-dimethylethylenediamine,60 ml. of N,N,N',N'-tetramethylethylenediamine and 10.96 g. ofleuco-1,4,5,8-tetrahydroxyanthraquinone is flushed with nitrogen andstirred under nitrogen for 2 hours while heating with an oil bath keptat 49°-51° C. The mixture is allowed to cool under nitrogen. The solidis collected and washed with ethanol giving 14.78 g. of the desiredproduct as a dark red-brown solid.

EXAMPLE 21,4-Bis[(2-dimethylaminoethyl)amino]-5,8-dihydroxyanthraquinone

A 12.00-g. portion ofleuco-1,4-bis[(2-dimethylaminethyl)amino]-5,8-dihydroxy-anthraquinone in100 ml. of nitrobenzene is heated under reflux for 15 minutes and thenfiltered while hot. The filtrate is reheated to boiling, allowed tocool, and the solid is collected and washed with ethanol giving 8.44 g.of the desired product as blue-black crystals, mp. 236°-238° C.

EXAMPLE 3Leuco-1,4-bis(2-morpholinoethylamino)-5,8-dihydroxyanthraquinone

A solution of 15.62 g. of N-(2-aminoethyl)morpholine in 40 ml. ofN,N,N',N'-tetramethylethylenediamine is de-aerated by bubbling nitrogenthrough it for 15 minutes. A 10.97-g. portion ofleuco-1,4,5,8-tetrahydroxyanthraquinone is added slowly with stirringand the suspension is treated as described in Example 1, giving 18.07 g.of the desired product as an olive solid, mpm 223°-227° C.

EXAMPLE 4 1,4-Bis(2-morpholinoethylamino)-5,8-dihydroxyanthraquinone

A 13.90-g. portion ofleuco-1,4-bis(2-morpholinoethylamino)-5,8-dihydroxy-anthraquinone in 100ml. of nitrobenzene is oxidized as described in Example 2 giving 10.30g. of the desired product as black rods, mp. 241°-243° C.

EXAMPLE 5Leuco-1,4-bis[(2-diethylaminoethyl)amino]-5,8-dihydroxyanthraquinone

The procedure of Example 3 is repeated using 13.95 g. ofN,N-diethylethylenediamine in place of the N-(2-aminoethyl)morpholine,giving 13.97 g. of the desired product as a red-brown solid, mp.182°-185° C.

EXAMPLE 6 1,4-Bis[(2-diethylaminoethyl)amino]-5,8-dihydroxyanthraquinone

A 10.90-g. portion ofleuco-1,4-bis[(2-diethylaminoethyl)amino]-5,8-dihydroxyanthraquinone isoxidized as described in Example 2 giving 6.35 g. of the desired productas blue-black needles, mp. 202°-204° C.

EXAMPLE 7Leuco-1,4-bis[2-(1-pyrrolidinyl)ethylamino]-5,8-dihydroxyanthraquinone

The procedure of Example 3 is repeated using 12.05 g. ofN-2-pyrrolidinoethylamine, in place of the N-(2-aminoethyl)morpholine,and 80 ml. of N,N,N',N'-tetramethylethylenediamine, giving 13.24 g. ofthe desired product as a red-brown solid, mp. 180°-185° C.

EXAMPLE 81,4-Bis[2-(1-pyrrolidinyl)ethylamino]-5,8-dihydroxyanthraquinone

An 8.61-g. portion ofleuco-1,4-bis[2-(1-pyrrolidinyl)ethyl)amino]-5,8-dihydroxyanthraquinoneis oxidized as described in Example 2. The reaction mixture isevaporated to dryness and the residue recrystallized from toluene,giving 5.12 g. of the desired product as blue-black crystals, mp.193°-196° C.

EXAMPLE 9Leuco-1,4-bis[2-(methylamino)ethylamino]-5,8-dihydroxyanthraquinone

The procedure of Example 7 is repeated using 8.90 g. ofN-methylethylenediamine in place of the N-2-pyrrolidinoethylamine,giving 13.73-g. of the desired product as a dark green solid, mp.157°-160° C.

EXAMPLE 10Leuco-1,4-bis[(3-dimethylaminopropyl)amino]-5,8-dihydroxyanthraquinone

Nitrogen is bubbled through an 80-ml. portion ofdimethylaminopropylamine for 15 minutes. A 10.97-g. portion ofleuco-1,4,5,8-tetrahydroanthraquinone is added slowly with stirring. Themixture is heated under nitrogen at 50°-52° C. for 2 hours and thenallowed to cool. The solid is collected and washed with cold ethanolgiving 5.59-g. of dark, orange-red crystals, mp. 115°-118° C.

EXAMPLE 111,4-Bis[(3-dimethylaminopropyl)amino]-5,8-dihydroxyanthraquinone

A suspension of 6.00-g. ofleuco-1,4-bis[(3-dimethylaminopropyl)amino]-5,8-dihydroxyanthraquinonein 60 ml. of N,N,N',N'-tetramethylethylenediamine is heated on a steambath under reflux while air is bubbled in for 12 hours. The solution iscooled, producing a solid which is collected and washed twice withheptane and once with petroleum ether. This solid is recrystallized byextracting with 350 ml. of hot heptane, filtering and concentrating to300 ml. Crystallization and washing with petroleum ether gives 3.72 g.of the desired product as black needles, mp. 154°-157° C.

EXAMPLE 12 Leuco-1,4-bis(2-aminoethylamino)-5,8-dihydroxyanthraquinone

A reaction mixture comprising 10.97-g. ofleuco-1,4,5,8-tetrahydroxyanthraquinone in 80 ml. of de-aeratedN,N,N',N'-tetramethylethylenediamine containing 7.22 g. ofethylenediamine is heated and stirred under nitrogen at 48°-50° C. forone hour. The mixture is allowed to stand under a slow flow of nitrogen,producing a solid which is collected and washed with ethyl acetate,acetonitrile and petroleum ether giving 13.8 g. of the desired productas a red-black solid.

EXAMPLE 13 Leuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone

A suspension of 10.97 g. of leuco-1,4,5,8-tetrahydroxyanthraquinone in ade-aerated solution of 8.90 g. of 1,3-diaminopropane in 80 ml. ofN,N,N',N'-tetramethylethylenediamine is stirred and heated at 49° C. forone hour under nitrogen, then allowed to cool. The resulting solid iscollected and washed with cold ethanol giving 14.21 g. of the desiredproduct as a black solid.

EXAMPLE 14Leuco-1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone

A suspension of 12.5 g. of 2-(2-aminoethylamino)ethanol in 40 ml. ofN,N,N',N'-tetramethylethylenediamine is stirred and de-aerated bybubbling nitrogen in for 15 minutes. A 10.97-g. portion ofleuco-1,4,5,8-tetrahydroxyanthraquinone is gradually added withstirring. The suspension is heated and stirred under nitrogen in an oilbath at 50°-52° C. for 5 hours. The mixture is allowed to stand and coolunder nitrogen for 12 hours. The solid is collected by decantation,macerated in ethanol, collected and washed with ethanol giving 15.06 g.of the desired product as a green-gray solid, mp. 129°-131° C.

EXAMPLE 15Leuco-1,4-bis[2-[di(β-hydroxyethyl)amino]ethylamino]-5,8-dihydroxyanthraquinone

A solution of 17.8 g. of N,N-di(2-hydroxyethyl)ethylenediamine in 100ml. of methanol is cooled with an ice bath, stirred, and de-aerated bybubbling in nitrogen for 15 minutes. A 10.97-gram portion ofleuco-1,4,5,8-tetrahydroxyanthraquinone is gradually added with stirringand continued cooling. The suspension is heated and stirred undernitrogen in an oil bath at 50°-52° C. for one hour and the mixture isthen allowed to stand and cool under nitrogen overnight. The solid iscollected and washed with ethanol giving 14.8 g. of a red-brown solid,m.p. 165°-168° C.

EXAMPLE 16 1,4-Bis[2-(methylamino)ethylamino]-5,8-dihydroxyanthraquinonedihydrochloride

To a suspension of 11.60 g. (0.03 mole ofleuco-1,4-bis[2-(methylamino)ethylamino]-5,8-dihydroxyanthraquinone in200 ml. of 2-methoxyethanol was added gradually with stirring 15 ml. of8 N ethanolic hydrogen chloride. The system was chilled with an ice bathand stirred as 7.50 g. (0.0305 mole) of chloranil powder was graduallyadded. The mixture was stirred overnight at room temperature and dilutedwith 600 ml. of ether. The solid was collected and washed withtetrahydrofuran. The product (14.16 g.) was recrystallized by dissolvingit in 130 ml. of water and adding 650 ml. of acetone to give 13.15 g. ofa blue-black solid.

EXAMPLE 171,4-Bis[2-(2-aminoethylamino)ethylamino]-5,8-dihydroxyanthraquinone

Following the general procedure of Example 3, a mixture of 10.97-g. ofleuco-1,4,5,8-tetrahydroxyanthraquinone, 80 ml. ofN,N,N',N'-tetramethylethylenediamine and 21.84-g. (0.24 mole) ofdiethylenetriamine soon gave a thick, congealed mass which preventedeffective stirring so the reaction time was extended to 24 hours. Themixture was allowed to cool and the supernatant liquid was decanted anddiscarded. A solution of the congealed mass in 100 ml. of methanol wasfiltered, then allowed to oxidize in the air for four days in apartially covered flask. The gelatinous mass which had separated becamesolid when the oxidation mixture was agitated with 200 ml. ofacetonitrile and then allowed to stand for one hour. After the solid wascollected and washed first with acetonitrile, then with ether, itamounted to 10.88 g. of a blue-black powder.

EXAMPLE 18 Leuco-1,4-bis(4-aminobutylamino)-5,8-dihydroxyanthraquinone

Following the general procedure of Example 3 but using 45 ml. of1,4-diaminobutane as the primary amine component, there was obtained12.20 g. of product as a dull grey-green solid.

EXAMPLE 19Leuco-1,4-bis[2-dimethylaminopropylamino]-5,8-dihydroxyanthraquinone

The reaction of 12.26 g. of 2-dimethylaminopropylamine with 10.97 g. ofleuco-1,4,5,8-tetrahydroxyanthraquinone in 100 ml. of ethanol for onehour by the procedure of Example 1 gives 7.29 g. of red-brown crystals.

EXAMPLE 20Leuco-1,4-bis[2-(2-methylaminoethylamino)ethylamino]-5,8-dihydroxyanthraquinone

To a solution of 14.10 g. of 1-methyl diethylenetriamine in 50 ml. ofethanol and 40 ml. of N,N,N',N'-tetramethylethylenediamine is added10.97 g. of leuco-1,4,5,8-tetrahydroxyanthraquinone as in Example 1. Themixture is heated at 50° and stirred under nitrogen for one hour,chilled with an ice bath, the solid collected and washed with coldethanol to give 7.23 g. of green-black crystals, m.p. 108°-111° C.

EXAMPLE 21Leuco-1,4-bis[2-(2-dimethylaminoethylamino)ethylamino]-5,8-dihydroxyanthraquinone

The reaction of N-(dimethylaminoethyl)ethylenediamine withleuco-1,4,5,8-tetrahydroxyanthraquinone by the procedure of Example 20gives the title compound.

EXAMPLE 22Leuco-1,4-bis[2-(1-piperazinyl)ethylamino]-5,8-dihydroxyanthraquinone

The procedure of Example 20 applied to 15.50 g. ofN-(2-aminoethyl)piperazine gives 3.92 g. of a black powder which doesnot melt by 350° C. and is discarded. The mother liquor and ethanolwashes, on standing and partly evaporating during two weeks in anunstoppered flask, deposit a solid which is collected and washed withethanol to give 6.19 g. of the title compound as a black solid, m.p.200°-203° C.

EXAMPLE 23 1,4-Bis(2-aminoethylamino)-5,8-dihydroxyanthraquinonedihydrochloride

Oxidation with chloranil of 28.25 g. of the product of Example 12 by theprocedure of Example 16 gives 29.66 g. of a crude, blue-black solidwhich is then extracted by stirring for 14 hours with 800 ml. of water.Solids are removed by centrifugation and the supernatant solutionfreeze-dried, leaving 16.38 g. of a blue-black solid which is unmeltedby 350° C.

EXAMPLE 241,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinoneDihydrochloride

Chloranil oxidation of 17.86 g. of the product of Example 14 by theprocedure of Example 16 gives (without recrystallization) 21.34 g. ofblue-black solid, m.p. 203°-205° C.

EXAMPLE 251,4-Bis[2-(2-methylaminoethylamino)ethylamino]-5,8-dihydroxyanthraquinoneTetrahydrochloride

The product of Example 20 (11.70 g.) is oxidized with chloranil by theprocedure of Example 16, giving 18.03 g. of blue-black solid, m.p.190°-203° C.

EXAMPLE 261,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone

In a modification of the synthesis of Example 14 the solvent used is 100ml. of ethanol. The mother liquor from the leuco product is allowed tostand for two weeks in an unstoppered flask, whereupon the oxidizedproduct separates. It is collected and washed with ethanol, thenrecrystallized from ethanol, giving blue-black crystals, m.p. 175°-177°C.

EXAMPLE 27Leuco-1,4-bis[3-(2-hydroxyethylamino)-1-propylamino]-5,8-dihydroxyanthraquinone

The procedure of Example 15 is used with a solution of 14.18 g. of2-(3-aminopropylamino)ethanol in 100 ml. of ethanol. The resultingsolution is filtered and the filtrate diluted with 300 ml. of ether,precipitating the product as a goo. After decantation of the supernatantsolution the goo is caused to crystallize by agitating it with 100 ml.of tetrahydrofuran. Washing with ethanol gives 12.56 g. of green-blacksolid, m.p. 101°-104° C.

EXAMPLE 281,4-Bis[3-(2-hydroxyethylamino)-1-propylamino]-5,8-dihydroxyanthraquinonedihydrochloride

Oxidation of 9.95 g. ofleuco-1,4-bis[3-(2-hydroxyethylamino)propylamino]-5,8-dihydroxyanthraquinonewith chloranil as in Example 16 gives 11.70 g. of a blue solid whichdoes not melt by 350° C.

EXAMPLE 29Leuco-1,4-bis[2-(3-hydroxy-1-propylamino)ethylamino)-5,8-dihydroxyanthraquinine

The procedure of Example 15 is paralleled with 14.18 g. ofN-(3-hydroxypropyl)ethylenediamine in 100 ml. of ethanol to give 14.63g. of red-brown crystals, m.p. 58°-60° C.

EXAMPLE 301,4-Bis[2-(3-hydroxy-1-propylamino)ethylamino]-5,8-dihydroxyanthraquinonedihydrochloride

Chloranil oxidation of 10.77 g. of the product of Example 29 by theprocedure of Example 16 yielded 11.64 g. of a dark blue solid, m.p.210°-216° C.

EXAMPLE 31Leuco-1,4-bis[2-(2-hydroxy-1-propylamino)ethylamino)-5,8-dihydroxyanthraquinone

With 14.18 g. of 1-(2-aminoethylamino)-2-propanol in 100 ml. of ethanolthe procedure of Example 15 yields 17.61 g. of green-black crystals,m.p. 50°-60° C.

EXAMPLE 321,4-Bis[2-(2-hydroxy-1-propylamino)ethylamino]-5,8-dihydroxyanthraquinonedihydrochloride

A filtered solution of 14.44 g. ofleuco-1,4-bis[2-(2-hydroxy-1-propylamino)ethylamino]-1,4-dihydroxyanthraquinonein 215 ml. of 2-methoxyethanol is oxidized with 7.65 g. of chloranil bythe procedure of Example 16, affording 16.75 g. of purple solid, m.p.177°-185° C.

EXAMPLE 33Leuco-1,4-bis[2-[2-(2-hydroxyethylamino)ethylamino]ethylamino]-5,8-dihydroxyanthraquinone

The procedure of example 15 used with a solution of 17.67 g. of2-[2-(2-aminoethylamino)ethylamino]ethanol in 100 ml. of methanol givesa solution which is filtered, then diluted with 300 ml. of ether,precipitating a goo which hardens on standing overnight. Hardening iscompleted by thorough maceration of the solid in the solvent. The solidis collected and washed with ether, yielding 16.82 g. of a green-blacksolid. This solid remains granular if stored at -25° C., but coalescesinto a solid cake if stored at 25° C.

EXAMPLE 341,4-Bis[2-[2-(2-hydroxyethylamino)ethylamino]ethylamino]-5,8-dihydroxyanthraquinonetetrahydrochloride

Chloranil oxidation of 12.10 g. of the product of Example 33 by themethod of Example 16, including three additional washings of the solidwith methanol, gives 12.46 g. of dark blue, solid product.

EXAMPLE 351,4-Bis[2-(2,3-dihydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinonedihydrochloride

By the procedure of Example 15 is a solution of 16.10 g. of3-(2-aminoethylamino)-1,2-propanediol [A. R. Surrey, C. M. Suter and J.S. Buck, J. Am. Chem. Soc., 74, 4102(1952)] in 100 ml. of methanol givesa goo which is separated from solvent by chilling with an ice bath, thendecanting. The goo is washed four times by stirring 1.5 hours at 25°with 100-ml. portions of methanol, chilling with an ice bath, thendecanting. A filtered solution of the goo in 280 ml. of 2-methoxyethanolis oxidized with 10.01 g. of chloranil by the method of Example 16. Theproduct is additionally washed with ethanol, giving 15.25 g. of ablue-black solid, m.p. 191°-193° C.

EXAMPLE 36Leuco-1,4-bis[2-(1-aziridino)ethylamino]-5,8-dihydroxyanthraquinone

With 10.33 g. of N-(2-aminoethyl)aziridine in 80 ml. ofN,N,N',N'-tetramethylethylenediamine the procedure of Example 15 gives astiff gum. The next day the supernatent solution is discarded, 100 ml.of ether is added and the gum periodically macerated therein for anotherday, when the gum is mostly hardened. Hardening is completed bymaceration during three washings of the solid with ether, giving 17.66g. of blue-black, granular powder.

EXAMPLE 37 1,4-Bis[2-(1-aziridino)ethylamino]-5,8-dihydroxyanthraquinone

To a suspension of 4.10 g. of the product of Example 36 in 40 ml. ofchlorodorm is added a solution of 1.74 g. of diethyl azodicarboxylate in25 ml. of chloroform. The mixture is stirred for 20 minutes, theresulting dark blue solution is filtered, and the filtrate is evaporatedat ≦30°. A solution of the residue in 40 ml. of chloroform is stirredfive minutes with 2 g. of decolorizing carbon, filtered and washedthrough with another 25 ml. of chloroform. Addition of 100 ml. of etherto the filtrates precipitates a gum which is eliminated bydecantation-filtration. The filtrates deposit crystals which are washedsparingly with acetone. The chloroform-ether mother liquor, chilled at-60° C., deposits a second crop of crystals which is washed with etherand with methanol. A solution of both crops of crystals in 20 ml. ofchloroform is stirred with decolorizing carbon, filtered, evaporated at≦25° C. to a volume of 5 ml., diluted with 20 ml. of ether, then chilledat -60° C. The resulting blue-black crystals, washed with ether, amountto 0.64 g., m.p. 168°-170° C. In thin-layer chromatography on silica gelthe product is moved as a blue spot bychloroform-triethylamine-methanol, 27/3/1 (ratios by volume).

EXAMPLE 381,4-Bis[2-[2-(1-morpholino)ethylamino]ethylamino]-5,8-dihydroxyanthraquinonetetrahydrochloride

A solution of 20.80 g. of N-(morpholinoethyl)ethylenediamine in 100 ml.of ethanol is used in the procedure of Example 15 to give a solutionwhich is filtered and diluted with 900 ml. of ether, precipitating agoo. The supernatent solution is decanted, the goo dissolved in 175 ml.of 2-methoxyethanol and oxidized with 5.29 g. of chloranil by the methodof Example 16, giving 17.7 g. of dark blue solid.

EXAMPLE 39Leuco-1,4-Bis[2-(acetamido)ethylamino]-5,8-dihydroxyanthraquinone

A solution of 12.26 g. of N-acetylethylene diamine in 100 ml. of ethanolin the procedure of Example 15 gives 15.27 g. of dark, red-brown solid,m.p. 125° C.

EXAMPLE 40 1,4-Bis[2-(acetamido)ethylamino]-5,8-dihydroxyanthraquinone

A suspension of 11.95 g. ofleuco-1,4-bis[2-(acetamido)ethylamino]-5,8-dihydroxyanthraquinone isoxidized with 6.76 g. of chloranil during 61 hours by the method ofExample 16, giving a very acidic hydrochloride salt which is vonvertedto the free base by four washings with water. Crystallization from 110ml. of dimethyl sulfoxide (boiling only 2 minutes and not attempting ahot filtration), then washing with dimethyl sulfoxide and with ethanolgives 7.76 g. of blue-black solid, m.p. 273°-274° C.

EXAMPLE 411,4-Bis[2-[N-(2-hydroxyethyl)triflouroacetamido]ethylamino]-5,8-dihydroxyanthraquinone

A suspension of 1.50 g. of1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone in75 ml. of ethyl trifluoroacetate and 75 ml. of methanol is stirred for10 minutes. Evaporation of the resulting solution in vacuo at 30° C.leaves a residue which is washed and macerated with methylene chloride,giving 2.11 g. of blue-black solid, m.p. 162° C.

EXAMPLE 421,4-Bis[2-amino-2-carboxyethylamino]-5,8-dihydroxyanthraquinone: 3/4HCl

To a solution of 6.23 g. of dl-α,β-diaminopropionic acid in 30 ml. ofwarm water is added 1.078 g. of lithium hydroxide and 60 ml. of dimethylsulfoxide. The system is flushed with nitrogen and 4.12 g. ofleuco-1,4,5,8-tetrahydroxyanthraquinone is added gradually withstirring. The mixture is stirred and heated with an oil bath at 50°,first for 15 hours under nitrogen, then for 21 hours as the initialproduct is oxidized by bubbling in a stream of air. Thin-layerchromatography on silica gel with methanol-water-concentrated ammonia(25/5/1 by volume) shows all the product spots to be blue when theoxidation is complete. After the mixture is cool the solids are removedby filtration and washed once with dimethyl sulfoxide-water (2/1).Addition of 400 ml. of methanol to the filtrates precipitates a solidwhich is collected and washed with methanol. Further washing with atotal of 13. ml. of 0.01 N aqueous acetic acid dissolves virtually allof the solid. Addition of 3 ml. of concentrated hydrochloric acid to theacetic acid filtrates precipitates a blue-black solid which is washedwith acetone to give 0.24 g. of the product.

EXAMPLE 43Leuco-1,4-bis[2-(2-methoxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone

An ethanol solution of N-(2-methoxyethyl)ethylendiamine (U.S. Pat. No.3,454,640) reacts in the procedure of Example 15 to give the titlecompound.

EXAMPLE 441,4-Bis[2-(1,3-oxazolidin-1-yl)ethylamino]-5,8-dihydroxyanthraquinone

A solution of 1.62 g. of 37% aqueous formaldehyde solution in 50 ml. ofwater is stirred overnight with 4.44 g. of1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone.The resulting solid is washed with water to give the product.

EXAMPLE 451,4-Bis[2-(tetrahydro-1,3-oxazin-1-yl)ethylamino]-5,8-dihydroxyanthraquinon

A solution of 1.62 ml. of 37% aqueous formaldehyde in 50 ml. of 0.4 Naqueous sodium hydroxide is stirred overnight with 5.45 g. of1,4-bis[2-(3-hydroxy-1-propylamino)ethylamino]-5,8-dihyroxyanthraquinonedihydrochloride. The product is obtained by washing the resulting solidwith water.

EXAMPLE 461,4-Bis[2-(1,3-oxazolidin-2-one-1-yl)ethylamino]-5,8-dihydroxyanthraquinone

A solution of 0.020 g. of sodium in 25 ml. of methanol is stirred andheated under reflux overnight with 75 ml. of diethyl carbonate and 4.44g. of1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone.The mixture is allowed to cool. It is stirred with 0.1 ml. of aceticacid, the solid is collected by filtration and washed with methanol togive the product.

EXAMPLE 471,4-Bis[2-(1,3-oxazin-2-one-1-yl)ethylamino]-5,8-dihydroxyanthraquinone

A solution of 0.48 g. of sodium in 25 ml. of methanol is stirred andheated overnight with 75 ml. of diethyl carbonate and 5.45 g. of1,4-bis[2-(3-hydroxy-1-propylamino)ethylamino]-5,8-dihydroxyanthraquinonedihydrochloride. After the mixture cools it is stirred with 0.1 ml. ofacetic acid. The solid product is collected by filtration and washedwith methanol and then with water.

EXAMPLE 481,4-Bis[2-[di(β-hydroxyethyl)amino]ethylamino]-5,8-dihydroxyanthraquinonedihydrochloride

Chloranil oxidation of 10.77 g. of the product of Example 15 by themethod of Example 16 gives 11.64 g. of a dark blue solid, m.p. 216° C.

EXAMPLE 49 Preparation of 50 mg. Tablets

    ______________________________________                                        Per Tablet                 Per 10,000 Tablets                                 ______________________________________                                        0.050 gm.                                                                              1,4-bis(3-aminopropylamino)-                                                                    500 gm.                                                     5,8-dihydroxyanthraquinone                                           0.080 gm.                                                                              Lactose           800 gm.                                            0.010 gm.                                                                              Corn Starch (for mix)                                                                           100 gm.                                            0.008 gm.                                                                              Corn Starch (for paste)                                                                          75 gm.                                            0.148 gm.                  1475 gm.                                           0.002 gm.                                                                              Magnesium Stearate (1%)                                                                          15 gm.                                            0.150 gm.                  1490 gm.                                           ______________________________________                                    

The 1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone, lactose andcorn starch (for mix) are blended together. The corn starch (for paste)is suspended in 600 ml. of water and heated with stirring to form apaste. This paste is then used to granulate the mixed powders.Additional water is used if necessary. The wet granules are passedthrough a No. 8 hand screen and dried at 120° F. The dry granules arethen passed through a No. 16 screen. The mixture is lubricated with 1%magnesium stearate and compressed into tablets in a suitable tabletingmachine.

EXAMPLE 50 Preparation of Oral Suspension

    ______________________________________                                        Ingredient                 Amount                                             ______________________________________                                        Leuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxy-                                                         500    mg.                                         anthraquinone                                                                 Sorbitol solution (70% N.F.)                                                                             40     ml.                                         Sodium benzoate            150    mg.                                         Saccharin                  10     mg.                                         Red dye                    50     mg.                                         Cherry flavor              50     ml.                                         Distilled water qs ad      100    ml.                                         ______________________________________                                    

The sorbitol solution is added to 40 ml. of distilled water and theleuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone issuspended therein. The saccharin, sodium benzoate, flavor and dye areadded and dissolved. The volume is adjusted to 100 ml. with distilledwater. Each ml. of syrup contains 5 mg. ofleuco-1,4-bis(3-aminopropylamino)-5,8-dihydroxyanthraquinone.

EXAMPLE 51 Preparation of Parenteral Solution

In a solution of 700 ml. of propylene glycol and 200 ml. of water forinjection is suspended 20.0 grams of1,4-bis[3-(dimethylamino)propylamino]-5,8-dihydroxyanthraquinonedihydrochloride with stirring. After suspension is complete, the pH isadjusted to 5.5 with hydrochloric acid and the volume is made up to 1000ml. with water for injection. The formulation is sterilized, filled into5.0 ml. ampoules each containing 2.0 ml. (representing 40 mg. of drug)and sealed under nitrogen.

EXAMPLE 521,4-Bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinonedisuccinate salt

A mixture of 222 mg. of1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone,118 mg. of succinic acid, and 50 ml. of ethanol is heated under refluxfor 30 minutes to give the title compound.

EXAMPLE 531,4-Bis[2-(3-hydroxypropylamino)ethylamino)-5,8-dihydroxyanthraquinonedimalate salt

A mixture of 228 mg. of1,4-bis[2-(3-hydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinone,134 mg. of DL-malic acid, and 50 ml. of ethanol is heated under refluxfor 30 minutes to give the title compound.

EXAMPLE 541,4-Bis[2-(2-hydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinonedilactate salt

A mixture of 228 mg. of1,4-bis[2-(2-hydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinone,120 mg. of 80% DL-lactic acid, and 10 ml. of ethanol is heated on asteam bath for 10 minutes, cooled, treated with 50 ml. of acetone andcooled to obtain the title compound.

EXAMPLE 55 Preparation of 50 mg. Tablets

    ______________________________________                                        Per Tablet                 Per 10,000 Tablets                                 ______________________________________                                        0.050 gm.                                                                              1,4-Bis[2-(2-hydroxyethyl-                                                                      500 gm.                                                     amino)ethylamino]-5,8-dihy-                                                   droxyanthraquinone dihydro-                                                   chloride                                                             0.080 gm.                                                                              Lactose           800 gm.                                            0.010 gm.                                                                              Corn Starch (for mix)                                                                           100 gm.                                            0.008 gm.                                                                              Corn Starch (for paste)                                                                          75 gm.                                            0.148 gm.                  1475 gm.                                           0.002 gm.                                                                              Magnesium Stearate (1%)                                                                          15 gm.                                            0.150 gm.                  1490 gm.                                           ______________________________________                                    

The1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinonedihydrochloride, lactose and corn starch (for mix) are blended together.The corn starch (for paste) is suspended in 600 ml. of water and heatedwith stirring to form a paste. This paste is then used to granulate themixed powders. Additional water is used if necessary. The wet granulesare passed through a No. 8 hand screen and dried at 120° F. The drygranules are then passed through a No. 16 screen. The mixture islubricated with 1% magnesium stearate and compressed into tablets in asuitable tableting machine.

EXAMPLE 56 Preparation of Oral Suspension

    ______________________________________                                        Ingredient               Amount                                               ______________________________________                                        1,4-Bis[2-(2-hydroxyethylamino)ethylamino]-                                                            500     mg.                                          5,8-dihydroxyanthraquinone dihydrochloride                                    Sorbitol solution (70% N.F.)                                                                           40      ml.                                          Sodium benzoate          150     mg.                                          Saccharin                10      mg.                                          Red dye                  50      mg.                                          Cherry flavor            50      ml.                                          Distilled water qs ad    100     ml.                                          ______________________________________                                    

The sorbitol solution is added to 40 ml. of distilled water and the1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinonedihydrochloride is suspended therein. The saccharin, sodium benzoate,flavor and dye are added and dissolved. The volume is adjusted to 100ml. with distilled water. Each ml. of syrup contains 5 mg. of1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinonedihydrochloride.

EXAMPLE 571,4-Bis[2-(3-hydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinonediacetate salt

A mixture of 228 mg. of1,4-bis[2-(3-hydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinone,60 mg. of glacial acetic acid, and 50 ml. of ethanol is heated underreflux for 30 minutes to give the title compound.

EXAMPLE 581,4-Bis[2-(2-hydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinonediacetate salt

A mixture of 228 mg. of1,4-bis[2-(2-hydroxypropylamino)ethylamino]-5,8-dihydroxyanthraquinone,60 mg. of glacial acetic acid, and 10 ml. of ethanol is heated on asteam bath for 10 minutes, cooled, treated with 50 ml. of acetone andcooled to obtain the title compound.

We claim:
 1. A compound selected from the group consisting of1,4-bis[2-(1,3-oxazolidin-1-yl)ethylamino]-5,8-dihydroxyanthraquinone,the leuco base and tautomer thereof, and the pharmaceuticallyacid-addition salts thereof.
 2. A compound selected from the groupconsisting of1,4-bis[2-(tetrahydro-1,3-oxazin-1-yl)ethylamino]-5,8-dihydroxyanthraquinone,the leuco base and tautomer thereof, and the pharmaceutically acceptableacid-addition salts thereof.
 3. A compound selected from the groupconsisting of1,4-bis[2-(1,3-oxazolidin-2-one-1-yl)ethylamino]-5,8-dihydroxyanthraquinone,the leuco base and tautomer thereof, and the pharmaceutically acceptableacid-addition salts thereof.
 4. A compound selected from the groupconsisting of1,4-bis[2-(tetrahydro-1,3-oxazin-2-one-1-yl)ethylamino]-5,8-dihydroxyanthraquinone,the leuco base and tautomer thereof, and the pharmaceutically acceptableacid-addition salts thereof.